S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Medicine (의학과) Theses (Ph.D. / Sc.D._의학과)
The Role of Interleukin 18 on Allergic Inflammation in Ovalbumin-Induced Allergic Rhinitis Murine Model
- 의과대학 의학과
- Issue Date
- 서울대학교 대학원
- 학위논문 (박사)-- 서울대학교 대학원 : 의학과, 2014. 2. 이재서.
- Interleukin 18 (IL18), originally known as potent interferon (IFN) γ-inducing activity, can both increase serum IgE levels and promote allergen-induced eosinophilic influx into the airways of mice used as models of asthma. In the ovalbumin (OVA)-induced asthma model, IL18 expression was upregulated in macrophages obtained from bronchoalveolar lavage fluid and airway epithelial cells. A combination of antigen with IL18-stimulated T helper (Th) type 1 cells can cause overproduction of IFNγ, IL9, IL13, macrophage inflammatory protein-1a, and granulocyte-macrophage colony-stimulating factor, and may thereby induce acute airway inflammation in asthma. The reports on IL18 in allergic rhinitis have been inconsistent with those on IL18 in allergic asthma. Increased level of IL18 in the nasal discharge of allergic rhinitis patients had been reported, which was not in allergic rhinitis animal model using BALB/c mice, unlike in the bronchoalveolar lavage fluid. The possible reason of these discrepancy in the nose and the lung was attributed to the complex control mechanism of IL18 secretion in vivo, and the different roles of this pro-inflammatory cytokine in allergic rhinitis and asthma. Taken together, the function of endogenous IL18 in allergic disease is not well defined, warranting the analysis of the effect of genetic ablation of IL-18 on experimentally induced allergic diseases.In this study, we investigated the impact of IL18 on the nasal mucosa in allergic rhinitis using IL18-deficient mice. Wild-type (C57BL/6) and IL18-deficient mice (C57BL/6-background) were sensitized by intra-peritoneal injection of OVA on days 0, 7, and 14, then challenged via the airway from days 21 to 27 using inhaled OVA solution (1 g/50 mL PBS) delivered using an ultrasonic nebulizer. The mice were sacrificed to analyze the severity of allergic rhinitis symptoms, tissue eosinophilic infiltration, the levels of mRNAs encoding Th1 and Th2 cytokines in nasal cells, Th1/Th2 cytokine levels in splenocyte culture supernatants, the time course of IL2/IL18 secretion by OVA, CD4+CD25+Foxp3+ splenocyte population and proliferation of CD4+ splenocytes by OVA-stimulation. Allergic inflammation, including tissue eosinophilic infiltration and allergic nasal symptoms, did not develop in the absence of IL18. IL12 were paradoxically overexpressed in peripheral organs lacking IL18 when the mice were sensitized to OVA. Splenocytes from sensitized IL18-deficient mice produced more IL2, and such overproduction was suppressed by exogenous IL18. CD4+CD25+Foxp3+ splenocytes expanded in OVA-sensitized/challenged wild-type mice, which was not in IL18-deficient mice. Furthermore, IL4+ and IFNγ+ cells proliferated upon OVA stimulation. These results imply that, during allergic inflammation, IL18 is assumed to be necessary for differentiation and immune regulatory function of allergen-induced CD4+CD25+Foxp+ Tregs. Locally, especially in the nose, this pro-inflammatory cytokine might modulate innate immune responses through IL2 regulation, to prevent exaggerated local inflammation by allergens. Possibly, the role of IL18 in allergic inflammation is to maintain immune homeostasis rather than to enhance Th1/Th2 response.